The present invention relates to therapeutic and diagnostic chemical agents, and more particularly to compounds that can bind to an opioid receptor while being conjugated to a therapeutically or diagnostically active group.
Studies of the binding of various ligands in brain and other tissues have revealed the presence of several distinct receptors that bind to opioid compounds.
Three major categories of opioid receptors in animals are recognized, and these are commonly designated as xcex4 (delta), xcexa (kappa) and xcexc (mu). Several review articles are available, which describe the research which elucidated the presence of these receptors, and the endogenous peptides and other compounds with which they interact. See, e.g., Akil et al., Annu. Rev. Neurosci. 7:223-255 (1984).
Three distinct families of peptides have been identified that interact with opioid receptors: the enkephalins, the endorphins, and the dynophins. Each family is derived from a distinct precursor polypeptide, designated proenkephalin, pro-opiomelanocortin (POMC), and prodynorphin, respectively. These peptides, and the precursors thereof, are generally found in viva associated with cells that mediate pain, however they may also be found associated with cells that regulate the autonomic nervous system and neuroendrocrinological functions, among others.
There are also numerous non-peptidic compounds that may serve as ligands for opioid receptors. Some compounds interact non-specifically with all opioid receptor types, while other compounds demonstrate a higher affinity for one receptor type than other types. Moreover, a compound may interact with a receptor as an agonist, a partial agonist, or an antagonist, at each receptor type. See, e.g., Martin, Pharmacol. Rev. 35:283-323 (1983). A discussion of many compounds, both peptidic and non-peptidic, which may serve as ligands for opioid receptors is found in Jaffe et al., Opioid Analgesics and Antagonists, Chapter 21 of Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 8th Ed. Ed. A. G. Gilman, T. N. Rall, A. S. Nies, P. Taylor. Pergamon Press (1990).
Opioid receptor ligands have been implicated in the mediation of many important physiological responses, including pain/analgesia, appetite, gastric secretion, epileptic seizures and other neurological disorders, renal function, cardiovascular responses, and traumatic paralysis, among others. Due to the physiological significance of opioid receptor ligands, extensive research has been conducted into developing new ligands which may be used in various therapies. See, e.g., U.S. Pat. Nos. 5,658,908; 5,631,263; 5,578,725; 5,552,404; 5,464,841; 5,455,230; 5,411,965; 5,352,680; 5,332,818; 5,298,622; 4,816,586; 4,649,200. See also Campa et al., Cancer Res. 56:1965-1701 (1996); Chang et al., PCT Published Application No. WO 93/15062; Chang et al., J. Pharm. Exp. Therap. 267,852-857 (1993); Dasher et al., J. Med. Chem. 35:2374-2384 (1992); Koolpe et al., J. Med. Chem. 28:949-957 (1985); Olmsted et al., J. Med. Chem. 36:179-180 (1993); Portoghese, J. Med. Chem. 35:4325-4329 (1992); Portoghese et al., J. Med. Chem. 35:4086-4091 (1992); Portoghese, TiPS Reviews 10:230-235 (1989); Portoghese et al., J. Med. Chem. 31:281-282 (1988); Portoghese, Eur. J. Pharm 146:185-186 (1988); Schmidhammer et al., Bioorganic and Med. Chem. Let. 7:151-156 (1997); Vogel et al., Int. J. Peptide Protein Res. 48:495-502 (1996); Weerawarna et al., J. Med. Chem. 37:2856-2864 (1994).
There is a need in the art for effective opioid receptor ligands which demonstrate specificity to one or more intended opioid receptors, and can deliver functional agents to the opioid receptor. The present invention fulfills this need and further provides other related advantages as disclosed herein.
In one aspect, the present invention provides a compound that includes a ligand portion (L) which has binding affinity for an opioid receptor, and a therapeutically or diagnostically effective group (X). The group (X) may be selected from, for example, radionuclide chelating agents, fluorochromes, toxins, drugs, polyboron moieties, proteins, biological response modifiers, chemical moieties capable of binding to other molecules of interest, and radioisotopes selected from therapeutically effective alpha and beta emitters, and diagnostically effective gamma emitters.
In another embodiment, the invention provides a therapeutic method using a compound described above. In this embodiment, a therapeutically effective amount of a compound of the invention is administered to a subject in need thereof, such that a compound of the invention binds to an opioid receptor. For instance, the invention provides a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention. The cancer may be small cell lung cancer or other neuroendrocrine cancer.
In another embodiment, the invention provides a diagnostic method using a compound described above. In this embodiment, a diagnostically effective amount of a compound of the invention is administered to a subject in need thereof, such that the compound binds to an opioid receptor. The compound may be administered within or outside of the central nervous system. In a related embodiment, the invention provides for an in vitro diagnostic method using a compound described above. In this related embodiment, a diagnostically effective amount of a compound of the invention is contacted in vitro with an opioid receptor.
These and related embodiments of the present invention will be apparent upon reference to the following drawings and detailed description.